PROJECT SUMMARY Women are more than twice as likely than men to develop Alzheimer?s disease (AD). Indeed, 2/3 of AD cases in the US are women despite an equal incidence of apolipoprotein-?4 genotype (APOE4), the major genetic AD risk factor, across genders. Thus far, few factors that influence this relationship in women have been discovered, in large part because there has not been a targeted, systematic evaluation of women?s risk in a comprehensive dataset. The goal of this project is to investigate interactions between gender and genetics, such as APOE4 gene dose, on brain morphometry, cognitive decline, and clinical conversion to AD. This project will leverage existing longitudinal cohorts from more than 2700 participants with longitudinal follow-up visits to evaluate the relationship between gender and genetic interactions on changes in brain morphometry, cognitive function, and clinical diagnosis using cohorts enriched for APOE4 homozygotes. Equipped with a large, harmonized dataset, we anticipate enriched scientific discovery of interactions between gender and genetic risk factors for Alzheimer?s disease following these specific goals: 1) Analyze differential brain deformation and cognitive decline by gender and genetic status, 2) Examine the predictive utility of subtle brain deformation on subsequent cognitive function and clinical progression by gender and genetic status, and 3) Conduct exploratory gender X genetic associations with AD risk and analysis of gender X APOE4 associations in ongoing clinical trials paradigms as proof-of-concept. With a rich accumulation of brain, cognitive, and clinical variables proposed in this study, we will carefully pursue scientific discovery of gender- specific AD phenotypes.